The Nitroaldol Reaction

The nitroaldol (Henry) reaction involves the addition of nitronates to aldehydes and ketones to give a P-nitroalcohol. These products are usefrd synthetic building blocks as the nitro group can be transformed into a range of other functional groups, and this has stimulated some recent research into the development of a catalytic asymmetric variant. Some of the catalyst systems used in the asymmetric aldol rection have been successfully employed in the catalytic asymmetric nitroaldol process. 

Silyl nitronates undergo enantioselective addition to aromatic aldehydes in the presence of an enantiomerically pure bifluoride derived from (7.103). In this approach the anti-adduct is the major diastereomer formed. Thus silyl nitronate (7.105) undergoes addition to benzaldehyde to give adduct (7.106) with high ee. Alternately the coupling of silyl nitronates can be achieved with high ee using Lewis acids such as copper bis-oxazoline catalyst (7.107) in combination with a fluoride 

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Intermolecular reaction of the mannose-derived 2,3-0-isopropylideiie-a-D-/y.vc>-pentodialdo-l,4-furanoside 13 affords a diastereomeric mixture of nitroalcohols 14. Upon fluoride-catalyzed desilylation, a stereoisomerically pure nitrocyclitol 15 was obtained from a successive intramolecular nitroaldol reaction as a consequence of the reversibility of the nitroaldol reaction which, in this case, allows the equilibration of isomers through open-chain intermediates33. 

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

Novel chiral thiolated amino alcohols have been recently synthesised and then evaluated by Vilaivan el al. as a potential new class of ligands for Cu-catalysed nitroaldol reactions. Amino alcohol ligands bearing Ai-(2-alkyl-thio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying Al-2-thienylmethyl substituents provided better enantioselectivities of up to 75% ee for the nitroaldol reaction between p-nitro-benzaldehyde and nitromethane. A range of aromatic aldehydes were acceptable substrates giving moderate to high enantioselectivities of up to 88% ee, as shown in Scheme 10.32. 

Molecular modeling studies revealed a similar binding mode for (5)-2-nitro-1 -phenylethanol in the catalytic center of ///)HNL as was determined experimentally for (5)-mandelonitrile, preserving all mechanistically important polar interactions with active-site residues. This implies that the mechanism for the cyanohydrin reaction applies to the nitroaldol reaction as well. 

The nitroaldol reaction of methyl nitroacetate (199, Scheme 38) with 1,2 3,4-di-0-isopropylidene-a-D-ga/acfo-hexodialdo-l,5-pyranose (200) and 2,3-O-isopropyli-dene-D-glyceraldehyde (202) catalyzed by silica gel proceeded in almost quantitative yield, with high selectivity for attack on the aldehyde carbonyl group, giving derivatives 201 and 203, respectively. Two of the four possible diastereomers were detected as main products, and were obtained as a mixture. For the nitroaldol reaction with 200 gave similar results in either the presence or absence of silica gel, whereas the reaction with 202 did not proceed in its absence, showing that catalytic action of silica is mandatory in this case.176... 

Although catalytic amounts of base proved sufficient for library generation, 10 equivalents were used in order to achieve a reasonable equilibration rate for the slightly different ratio between the quantities of aldehydes and nihoalkane (5 1). Furthermore, these benzaldehydes were chosen in view of their similar individual reactivity in the nitroaldol reaction, resulting in close to isoenergefic behavior in the produced DCL. 

The nitroaldol reaction, particularly involving ketones has been relatively unexplored in the field of asymmetric organocatalysis. Employing cupreines and cupreidines as catalysts, Deng [63] presented an enantioselective nitroaldol reaction of a-ketoesters... 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

Scheme 6.173 Proposed transitions-state geometry for the nitroaldol reaction of nitroalkanes with a-ketoesters in the presence of (S,S)-configured guanidine thiourea 183.

Other major homologation processes are the nitroaldol reaction, arising from the reaction between a nitronate anion and a carbonyl compound, and a Michael addition reaction. 

The nitroaldol reaction of silyl nitronates with aldehydes promoted by ammonium fluorides, which was originally introduced by Seebach and Colvin in 1978 [24], is a useful method for the preparation of 1,2-functionalized nitroalkanols. Recently, the present authors have succeeded in developing an asymmetric version of high efficiency and stereoselectivity by using a designer chiral quaternary ammonium bifluoride of type 6 as catalyst, which was readily prepared from the corresponding bromide by the modified method C in Scheme 9.5 [25]. 

Chiral guanidinium-based ligands have also been used for recognition of diastereomeric salts of saccharides [45]. Some promising ligands with guani-dinium structure have not been studied yet [46], and some of them have been used as catalysts for the nitroaldol reaction [47] and Michael addition to a,P-unsaturated ketones [48]. 

Strongly chelating ligands provide a sterically rigid ligand frame, a prerequisite for induction of asymmetry at the lanthanide center. Complexes derived from (S)-( — )-BINOL were thoroughly studied in the nitroaldol reaction (Henry reaction, Scheme 27) [250]. 

The jyn-selective asymmetric nitroaldol reaction was successfully applied to the catalytic, asymmetric synthesis of ftireo-dihydrosphingosine (94), which elicits a variety of cellular responses by inhibiting protein kinase C (Figure 22).44 The nitroaldol reaction of hexadecanal 92 with 3 equiv. of nitroethanol (86) in the... 

In the preparation of dynamic nitroaldol systems, different aldehydes and nitroalkanes were first evaluated for reversible nitroaldol reactions in the presence of base to avoid any side- or competitive reactions, and to investigate the rate of the reactions. 1H-NMR spectroscopy was used to follow the reactions by comparison of the ratios of aldehyde and the nitroalcohols. Among various bases, triethylamine was chosen as catalyst because its reactions provided the fastest exchange reaction and proved compatible with the enzymatic reactions. Then, five benzaldehydes 18A-E and 2-nitropropane 19 (Scheme 9) were chosen to study dynamic nitroaldol system (CDS-2) generation, because of their similar individual reactivity and product stabilities in the nitroaldol reaction. Ten nitroaldol adducts ( )-20A-E were generated under basic conditions under thermodynamic control, showing... 

Thus, reaction of (34) with a 30% aqueous solution of formaldehyde proceeds at room temperature, in the presence of potassium carbonate, allowing (35), in respectable yields, regardless of the ring size of cycloalkanones (34). Probably, the synthesis involves, firstly, the nitroaldol reaction of (34) with formaldehydes, followed by ring cleavage of the formed nitroalkanol promoted by water, then further nitroaldol reaction with a further molecule of formaldehyde. 

It seems that the syn selectivity in the nitroaldol reaction can best be explained as arising from steric hindrance in the bicyclic transition state it seems that the greater stereoselectivity obtained by use of catalysts 27 and 28 can be ascribed to increased catalyst stability, even in the presence of an excess of highly acidic nitroalkanes. The syn-selective asymmetric nitroaldol reaction was successfully applied to the catalytic asymmetric synthesis of t/zreo-dihydrosphingosine 45, which elicits a variety of cellular responses by inhibiting protein kinase C. An efficient synthesis of erythro-AHPA 42 from L-phenylalanine was, moreover, achieved by using LLB (Sch. 9) [59],... 

In the preparation of polyhydroxylated azepane as potential glycosidase inhibitors, Dha-vale [28] described a short synthetic route utilizing the Henry approach. The nitroaldol reaction of l,2-0-isopropylidene-3-0-benzyl-a-D-xylo-pentodialdose 36 and nitromethane in the presence of triethylamine at room temperature afforded a-D-gluco- and /3-L-ido- nitroal-dose 37, the precursors to (2S, 3R, 4R, 5R) and (2S, 3R, 4R, 55) tetrahydroxyazepanes 38 and 39, in a 88 12 ratio in 95% yield (O Scheme 13). 

Diols The nitroaldol reaction is followed by ring cleavage in the cases of a-nitrocycloalkanones. 

Condensation reactions. The nitroaldol reaction and formation of benzimidazoles from o-phenylenediamine and aldehydes are ctirried out in silica gel support with microwave irradiation. The latter preparation also includes nitrobenzene or dimethyl sulfoxide for dehydrogenating the initial condensation products. 

Nanostructured heterogeneous catalysts were prepared by supporting amines on silica-alumina materials (SA-NR2) via post-modification methodology. The promising adjacent position of acid and base sites on the SA-NR2 allowed high catalytic activity for various organic transformations such as cyanoethoxycarbonylation (Scheme 3.38 route a) and the nitroaldol reaction (Scheme 3.38 route b). ... 

First encouraging results for a stereoselective synthesis in general were reported by Seebach in 1982, who investigated the syn/anti-diastereoselectivity starting from achiral aldehydes and nitroalkanes [4,5]. Barrett et al. examined the influence of nonchiral Lewis acids on the syn/anti diastereoselectivity [6]. Stoichiometric amounts of an enantiomerically pure aldehyde were used in a di-astereoselective reaction with 3-nitropropionate by Hanessian et al. [7]. However, an approach to enantioselective synthesis of nitroalcohols via the route of the asymmetric Henry reaction could not be carried out until almost one hundred years after the discovery of the nitroaldol reaction. 

However, structural modification of the BINOL ligand system also plays an important role with regard to stereoselection in the asymmetric Henry reaction. Improved enantioselectivites were obtained using a number of (P)-BINOL derivatives 8 (3 mol equiv) in which the 6,6 -positions were substituted [21 ]. Their utility as asymmetric catalysts was assessed using the nitroaldol reaction of ni-tromethane with hydrocinnamaldehyde 1. Enantioselectivities up to 88% ee accompanied by chemical yields up to 85% were obtained using 3.3 mol % of various catalysts 9 and 10 equiv of nitromethane (-40 °C, 91 h) (Scheme 4). 

The Henry reaction is an aldol-type reaction between a nitroalkane and an aldehyde in the presence of a base. Since basic reagents are also catalysts for the aldol condensation, the nitroaldol reactions must be strictly controlled. An interesting alternative lies in the use of surfactants to perform the reaction in an aqueous medium [63], The Reformatsky reaction, which involves a-haloketones and aldehydes, can be mediated by zinc, tin or indium in water in the latter case the proportion of undesirable reduction products could be strongly reduced [64]. 

GENERAL CONSIDERATIONS ON THE NITROALDOL REACTION AND ITS UTILITY IN ORGANIC 322 SYNTHESIS... 

Regio- and Stereo-selectivity in the Nitroaldol Reaction with afi-Unsaturated Aldehydes and Ketones 330... 

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